Elp fusion proteins for controlled and sustained release

Abstract

The present disclosure provides pharmaceutical formulations for sustained release, and methods for delivering a treatment regimen with a combination of sustained release and long half-life formulations. The disclosure provides improved pharmacokinetics for peptide and small molecule drugs.

1 . A sustained release pharmaceutical formulation comprising:
 a therapeutic agent for systemic administration, the therapeutic agent comprising an active agent and at least 90 elastin-like peptide (ELP) structural units selected from any one of SEQ ID NOs: 1-13, wherein X is selected from Val, Gly, and Ala,   wherein each X is selected from V, G, and A, and wherein the ratio of V:G:A is selected from the group consisting of about:
 a) 7:2:0; 
 b) 7:0:2; 
 c) 6:0:3; 
 d) 5:2:2; and 
 e) 5:0:4 
   and   one or more pharmaceutically acceptable excipients.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the formulation provides slow absorption from an injection site upon administration. 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the formulation provides a flat PK profile upon administration, as compared to the PK profile for the active agent in the absence of the amino acid sequence forming a reversible matrix. 
     
     
         4 . The pharmaceutical formulation of  claim 3 , wherein the PK profile has a shallow Cmax and/or low ratio of peak to trough and/or long Tmax. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein formation of a reversible matrix at body temperature reverses as protein concentration decreases. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the ELP comprises [VPGXG] 144 . 
     
     
         7 . (canceled) 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein the subject is human. 
     
     
         9 . The pharmaceutical formulation of  claim 1 , wherein the subject is a non-human mammal. 
     
     
         10 . The pharmaceutical formulation of  claim 1 , wherein the active agent is a protein. 
     
     
         11 . The pharmaceutical formulation of  claim 10 , wherein the therapeutic agent is a recombinant fusion protein between the protein active agent and ELP. 
     
     
         12 . The pharmaceutical formulation of  claim 10 , wherein the protein active agent has a circulatory half-life in the range of from about 30 seconds to about 10 hour, or about 30 seconds to about 1 hour. 
     
     
         13 . The pharmaceutical formulation of  claim 10 , wherein the protein active agent is a GLP-1 receptor agonist or derivative thereof, a VPAC2 selective agonist or a derivative thereof, a GIP receptor agonist or a derivative thereof, a glucagon receptor agonist or a derivative thereof, exendin-4 or a derivative thereof, or insulin or a derivative thereof. 
     
     
         14 . The pharmaceutical formulation of  claim 13 , wherein the formulation is a co-formulation comprising at least two of a GLP1 receptor agonist, a glucagon receptor agonist, a GIP receptor agonist, exendin-4, and insulin. 
     
     
         15 . The pharmaceutical formulation  claim 1 , wherein the therapeutic agent is a chemical conjugate between the active agent and ELP. 
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein the active agent is a chemotherapeutic agent, such as a chemotherapeutic agent selected from methotrexate, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, fluorouracil, verapamil, cyclophosphamide, cytosine arabinoside, aminopterin, bleomycin, mitomycin C, democolcine, etoposide, mithramycin, chlorambucil, melphalan, daunorubicin, doxorubicin, tamoxifen, paclitaxel, vinblastine, camptothecin, actinomycin D, cytarabine, and combrestatin. 
     
     
         17 . The pharmaceutical formulation of  claim 1 , wherein the therapeutic agent is present in the range of about 0.5 mg/mL to about 200 mg/mL. 
     
     
         18 . The pharmaceutical formulation of  claim 17 , wherein the therapeutic agent is present in the range of about 30 mg/mL to about 150 mg/mL. 
     
     
         19 . The pharmaceutical formulation of  claim 18 , wherein the therapeutic agent is present in the range of about 50 mg/mL to about 125 mg/mL, or about 75 mg/mL to about 110 mg/mL. 
     
     
         20 . The pharmaceutical formulation of  claim 19 , wherein the therapeutic agent is present in the amount of about 100 mg/mL. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent does not form a phase-transitioned matrix at storage conditions. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the storage conditions are less than about 40° C., or less than about 37° C., less than about 30° C., less than about 27° C., or less than about 25° C. 
     
     
         23 . The pharmaceutical formulation of  claim 22 , wherein the formulation is stable for more than 1 month at the storage conditions. 
     
     
         24 . The pharmaceutical formulation of  claim 23 , wherein the formulation is stable for more than about 1 month at about 25° C. 
     
     
         25 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises two or more of calcium chloride, magnesium chloride, potassium chloride, potassium phosphate monobasic, sodium chloride, polysorbate 20, sodium phosphate, sodium phosphate monobasic, and sodium phosphate dibasic. 
     
     
         26 . The pharmaceutical formulation of  claim 25 , wherein the formulation comprises sodium phosphate, sodium chloride and polysorbate 20. 
     
     
         27 . The pharmaceutical formulation of  claim 26 , wherein the formulation comprises 10 mM sodium phosphate, 110 mM sodium chloride, and 0.1% polysorbate 20. 
     
     
         28 . The pharmaceutical formulation of  claim 1 , wherein the formulation is packaged in the form of pre-dosed pens or syringes for administration about once per week, about twice per week, or from one to eight times per month. 
     
     
         29 - 52 . (canceled) 
     
     
         53 . A method for delivering a sustained release regimen of a therapeutic agent, comprising, administering the formulation of  claim 1  to a subject in need, wherein the formulation is administered from about 1 to about 8 times per month. 
     
     
         54 . The method of  claim 53 , wherein the therapeutic agent is administered about 1 to about 8 times per month. 
     
     
         55 . The method of  claim 53 , wherein the formulation is administered about weekly. 
     
     
         56 . The method of  claim 53 , wherein the formulation is administered subcutaneously or intramuscularly. 
     
     
         57 . The method of  claim 53 , wherein the site of administration is not a pathological site.